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Clinical Review & Education

JAMA | Review

Celiac Disease and Nonceliac Gluten Sensitivity A Review

Maureen M. Leonard, MD, MMSc; Anna Sapone, MD, PhD; Carlo Catassi, MD, MPH; Alessio Fasano, MD

IMPORTANCE The prevalence of gluten-related disorders is rising, and increasing numbers of individuals are empirically trying a gluten-free diet for a variety of signs and symptoms. This review aims to present current evidence regarding screening, diagnosis, and treatment for celiac disease and nonceliac gluten sensitivity.

OBSERVATIONS Celiac disease is a gluten-induced immune-mediated enteropathy characterized by a specific genetic genotype ( HLA-DQ2 and HLA-DQ8 genes) and

autoantibodies (antitissue transglutaminase and antiendomysial). Although the inflammatory process specifically targets the intestinal mucosa, patients may present with gastrointestinal signs or symptoms, extraintestinal signs or symptoms, or both, suggesting that celiac disease is a systemic disease. Nonceliac gluten sensitivity

is diagnosed in individuals who do not have celiac disease or wheat allergy but who

have intestinal symptoms, extraintestinal symptoms, or both, related to ingestion of gluten-containing grains, with symptomatic improvement on their withdrawal. The clinical variability and the lack of validated biomarkers for nonceliac gluten sensitivity make

establishing the prevalence, reaching a diagnosis, and further study of this condition difficult. Nevertheless, it is possible to differentiate specific gluten-related disorders from other conditions, based on currently available investigations and algorithms. Clinicians cannot distinguish between celiac disease and nonceliac gluten sensitivity by symptoms, as they are similar in both. Therefore, screening for celiac disease must occur before

a gluten-free diet is implemented, since once a patient initiates a gluten-free diet, testing for celiac disease is no longer accurate.

CONCLUSIONS AND RELEVANCE Celiac disease and nonceliac gluten sensitivity are common. Although both conditions are treated with a gluten-free diet, distinguishing between celiac disease and nonceliac gluten sensitivity is important for long-term therapy. Patients with celiac disease should be followed up closely for dietary adherence, nutritional deficiencies, and the development of possible comorbidities.

JAMA . 2017;318(7):647-656. doi:10.1001/jama.2017.9730

JAMA . 2017;318(7):647-656. doi : 10.1001/jama.2017.9730 CME Quiz at Author Affiliations:

Author Affiliations: Center for Celiac Research and Treatment, Division of Pediatric Gastroenterology and Nutrition, MassGeneral Hospital for Children, Boston, Massachusetts (Leonard, Sapone, Catassi, Fasano); Celiac Research Program, Harvard Medical School, Boston, Massachusetts (Leonard, Sapone, Catassi, Fasano); Shire, Lexington, Massachusetts (Sapone); European Biomedical Research Institute Salerno, Salerno, Italy (Catassi, Fasano); Department of Pediatrics, Università Politecnica delle Marche, Ancona, Italy (Catassi).

Corresponding Author: Alessio Fasano, MD, Center for Celiac Research and Mucosal Immunology and Biology Research Center, Massachusetts General Hospital East, Bldg 114, 16th St (Mail Stop 114-3503), Charlestown, MA 02129-4404 (

Section Editors: Edward Livingston, MD, Deputy Editor, and Mary McGrae McDermott, MD, Senior Editor.

C eliac disease is a chronic, small-intestinal immune- mediated enteropathy initiated by exposure to dietary gluten in genetically predisposed individuals and charac-

terized by specific autoantibodies against tissue transglutaminase 2 (anti-tTG2), endomysium, and/or deamidated gliadin peptide. 1 Although up to 40% of the population carries the genotype HLA-DQ2 or HLA-DQ8 , which is required for the development of celiac dis- ease, only 2% to 3% of HLA-DQ2 or HLA-DQ8 carriers subsequently develop celiac disease. 2 Celiac disease, once considered a rela- tively rare gastrointestinal condition affecting almost exclusively young white children, can develop at any age and can affect almost any race. Celiac disease was first described by Samuel Gee in 1887. Wheat was hypothesized as the possible offending agent by William Dicke in 1941. 3

The epidemiology, clinical presentation, pathophysiology, and management of the disease have changed since its initial descrip-

tion. There is strong evidence that celiac disease is an autoimmune disease triggered by the ingestion of gluten present in wheat, bar- ley, and rye in genetically predisposed individuals. The prevalence of celiac disease in the general population is 1%, with regional dif-

ferences (Table 1). 4 Celiac disease can affect any human organ or tis- sue (Table 1 and Table 2 ). 6 Nonceliac gluten sensitivity is a term used to describe individu- als who have intestinal signs or symptoms, extraintestinal signs or symptoms, or both, related to ingestion of gluten-containing grains (Table 2), with improvement when these are removed from


patient’s diet. The frequency of nonceliac gluten sensitivity


unknown owing to the lack of validated biomarkers, but it is

thought to be more common than celiac disease. Wheat allergy, the third gluten-related disorder, which will not be addressed in this review, is defined as an adverse type-2 helper T-cell immunologic reaction to wheat proteins and typically presents soon after wheat

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Celiac Disease and Nonceliac Gluten Sensitivity

Table 1. Prevalence of Celiac Disease in the General Population and in At-Risk Groups a


Prevalence, %

General Population









Burkina Fasu


















The Netherlands


New Zealand














United Kingdom


United States


Mean (weighted)


At-Risk Groups

Type 1 diabetes


Autoimmune thyroid disease


Autoimmune liver disease


Down syndrome


Turner syndrome


Williams syndrome


IgA deficiency


IgA nephropathy


Juvenile idiopathic arthritis


a Modified from Husby et al. 4 Data on at-risk groups were collected from different, Western populations. 5 A prevalence range indicates that more than 1 study is available.

ingestion, with signs of anaphylaxis such as swelling or itching of the mouth, throat, and skin; nasal congestion; watery eyes; and dif- ficulty breathing. Wheat allergy is more common in children, with reported prevalence between 2% and 9% in children and 0.5% and 3% in adults. 8 This review provides an evidence-based update of the patho- physiology, diagnosis, treatment, and implications of celiac dis- ease and nonceliac gluten sensitivity.

of celiac dis- ease and nonceliac gluten sensitivity. Methods The Cochrane Library (January 15, 2010, to
of celiac dis- ease and nonceliac gluten sensitivity. Methods The Cochrane Library (January 15, 2010, to


The Cochrane Library (January 15, 2010, to April 10, 2017), MEDLINE (January 15, 2010, to April 10, 2017), and Google

Scholar (January 15, 2010, to April 18, 2017) were searched using the search terms coeliac , celiac , non-celiac , non-coeliac , gluten , and wheat sensitivity , alone and in combination. Publications in the past 5 years were selected in addition to commonly refer- enced and highly regarded older publications. Reference lists of articles identified by this search strategy were selected. Review articles and book chapters were cited to provide readers with additional details and sources of additional references.

additional details and sources of additional references. Results Pathophysiology Gluten as Environmental Trigger of
additional details and sources of additional references. Results Pathophysiology Gluten as Environmental Trigger of



Gluten as Environmental Trigger of Gluten-Related Disorders

Gluten is a mixture of gliadins and glutenins, complex pro- teins unusually rich in prolines and glutamines that are not completely digestible by intestinal enzymes. 9 The final product of this partial digestion is a mix of peptides that can trigger host responses (increased intestinal permeability and innate +/− adaptive immune response) that closely resemble those instigated by the exposure to gastrointestinal pathogens 10-13

( Figure 1 ).

Normal Phsyiologic Events That Contribute to the Pathogenesis of Celiac Disease and Nonceliac Gluten Sensitivity

Gluten Translocation From Lumen to Lamina Propria (Paracellular vs

Transcellular) | Previous studies have shown that gliadin can cause an immediate and transient increase in gut permeability. 9,13 This permeating effect is secondary to the binding of spe- cific undigestible gliadin fragments to the CXCR3 chemokine receptor with subsequent release of zonulin, a modulator of inter- cellular tight junctions (Figure 1). 14 This process takes place in all individuals who ingest gluten. For the majority, these events do not lead to abnormal consequences. However, these same events can lead to an inflammatory process in genetically predisposed individuals when the immunologic surveillance system mistakenly recognizes gluten as a pathogen. Thus, this normal physiologic process is also essential to the development of celiac disease and nonceliac gluten sensitivity in at-risk individuals. Additionally, there is evidence that during the acute phase of celiac disease, gluten can also cross the intestinal barrier through the transcellu- lar pathway via transferrin receptor CD71, once tolerance to glu- ten has been lost 15 (Figure 1).

The Innate Immune Response | Innate immunity plays a critical role in initiating celiac disease and possibly nonceliac glu- ten sensitivity. Cytokines such as interleukin (IL) 15 and interferon alfa can prime the innate immune response by polarizing dendritic cells and intraepithelial lymphocyte function. 15,16 These mucosal events, along with the breach of the epithelial barrier function secondary to the gliadin-mediated zonulin re- lease, 14 lead to the passage of undigested peptides from the gut lumen to the lamina propria. Once gliadin crosses the epithelial barrier, neutrophil recruitment through IL8 pro- duction 11,12,17 or a direct neutrophil chemoattractant effect 18 causes a loss of tolerance to gluten in genetically susceptible in- dividuals (Figure 1).

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Celiac Disease and Nonceliac Gluten Sensitivity

Specific Events in Celiac Disease Pathogenesis

The Celiac Disease Adaptive Immune Response

The adaptive immune response is the consequence of a highly spe- cific interplay between selected gluten peptides and major histo- compatibility complex class II HLA-DQ2/8–restricted T-cell anti- gens and plays a role in celiac disease pathogenesis. 19,20 The contact of CD4 + T cells in the lamina propria with gluten induces their acti- vation and proliferation, leading to production of proinflammatory cytokines,metalloproteases, and keratinocyte growth factor, which induces cryptal hyperplasia and villous blunting secondary to intes- tinalepithelial cell death induced by intraepithelial lymphocytes. 20,21 Celiac disease crypt hyperplasia has been hypothesized to be the con- sequence of an imbalance between continuous tissue damage due to the mucosal autoimmune insult described above and inability of the stem cells to compensate (Figure 1).

Specific Events in Nonceliac Gluten Sensitivity Pathogenesis

The pathophysiology of nonceliac gluten sensitivity remains largely undetermined.In addition to gluten, α-amylase/trypsin inhibitors are suggested to play akey role in the innate immune response of gluten- related disorders. 22 A study by Sapone et al 23 found that gluten- sensitive individuals without celiac disease have a significant reduc- tion in T-regulatory cellmarkers compared with control patients and patients with celiac disease and an increase in the α and β classes of intraepithelial lymphocytes, with no increase in adaptive immunity- related gut mucosal gene expression. These findings suggest an im- portant role of the intestinal innate immune system in the patho- genesis of nonceliac gluten sensitivity without an adaptive immune response. 24 This hypothesis is also supported by the lack of enter- opathy with villous blunting in nonceliac gluten sensitivity, a fea- ture detected in celiac disease as a sign of HLA-driven adaptive immune response.

Clinical Presentation

Celiac Disease

Historically, the classic presentation of celiac disease had been mal- absorption manifesting as diarrhea and poor growth in child- hood. 25 It was presumed that the disease appeared when gluten was introduced, and the timing of the presentation of symptoms varied according to the intensity of the immune response. How- ever, the development of highly sensitive and specific noninvasive tests 6,26 facilitated a more accurate measurement of celiac disease prevalence, identified at-risk individuals and groups, and helped to establish that celiac disease is a systemic autoimmune disease and that onset can occur at any age, 27 presenting with gastrointes- tinal manifestations, extraintestinal manifestations, or both (Table 2). 28,29

Intestinal Manifestations

Gastrointestinal symptoms are more common in the pediatric age group. Children younger than 3 years are likely to present with di- arrhea, loss of appetite, abdominal distention, and poor growth. 30 Older children and adults may present with diarrhea, bloating, con- stipation, abdominal pain, or weight loss. 31,32

Extraintestinal Manifestations

Theetiology ofextraintestinalmanifestations isattributable toa com- bination of chronic inflammation, nutrient deficiencies, and possi-

Review Clinical Review & Education

Table 2. Gastrointestinal and Extraintestinal Manifestations of Celiac Disease and Nonceliac Gluten Sensitivity a


Presence of Symptoms


Nonceliac Gluten


Celiac Disease b



Abdominal pain, %

+ (27.8)







Constipation, %

+ (20.2)


Diarrhea, %

+ (35.3)





Lactose intolerance




Gastroesophageal reflux


Weight loss





Anemia, %

+ (32)





Arthralgia, %

+ (29.3)


Arthritis, %

+ (1.5)





Dental enamel hypoplasia


Delayed puberty


Dermatitis herpetiformis





Elevated liver enzymes


Rash (eg, eczema)



Fatigue, %

+ (26.3)


Cloudiness of consciousness







+ (1.5)




Iron-deficiency anemia


Mouth sores





Osteoporosis, %

+ (5.5)



Peripheral neuropathy, %

+ (0.7)


Short stature, %

+ (1.0)

a Sources: Lionetti and Catassi 5 and Fasano et al. 6

b Prevalence of celiac disease at presentation indicated in parentheses where available. 5,7

bly an adaptive immune response spreading from the intestinal mu- cosa to other tissues and organs. Poor growth, short stature, or delayed puberty may be the only presenting symptoms of pediat- ric celiac disease. 6 Dental enamel defects are common in children who develop celiac disease before age7 years. 33 Iron-deficiency ane- mia is a common presentation of celiac disease and is seen in 32% of adults and 9% of children. 7,34,35 In women, studies suggest an in- creased risk of miscarriage. 36,37 In addition to dermatitis herpeti- formis, dermatologic conditions such as urticaria, psoriasis, and dry skin are more frequent in patients with celiac disease. 38 Up to 22%

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Celiac Disease and Nonceliac Gluten Sensitivity

Figure 1. Mucosal Innate and Adaptive Immune Responses Involved in Celiac Disease Pathogenesis


Overview of structural changes in the intestinal mucosa in celiac disease

Normal duodenal mucosa Celiac disease enteropathy Villous atrophy LUMLUL U E NN LUMEN Epithelium Crypt
Normal duodenal mucosa
Celiac disease enteropathy
Villous atrophy
Crypt hyperplasia
Inflammatory cells
Normal duodenal mucosa
Duodenal mucosa in celiac disease
Gluten fragment
Gluten fragment
Secretory IgA–bound
gluten fragment
CD71 in apical
ofof zonuliulinn
oof tigghtht junjunjunjununununctictioonnn
Damaged IEC
Increased intestinal
TTrraansnsnsnsccellelelellelelll ulaulaulullarr
ooof glugluglglglglglug uteteteten
frafrafragmegmmmmemmmmm ntntntntsssss
oofoff gglululuttttennn
Increase in IEL
lymphocyte (IEL)
frafrafrafrar gmgmmemenntsts
CD71 in
basal position
Immune response in celiac disease
Innate immune response
Adaptive immune response
Environmental factors
Mucosal inflammation
Gluten fragments
NK cell
Genetic susceptibility
to epithelium
T H 1 cell
(NK cell)
Increase in IEL
IL-15 release
T H 1
B cell
CD4 +
T cell
B cell proliferation
and differentiation
of neutrophils
CD4 +
T H 2
B cell
T cell
CD4 +
T cell

A, Mucosa with normal 3:1 villous-crypt ratio (left) and with structural features of celiac disease (right). B, Competent tight junctions and CD71 receptor expressed on IEC basal membrane. C, Specific undigested gluten fragments bind to CXCR3 receptor with subsequent release of zonulin and increased paracellular passage of gluten fragments. D, In genetically susceptible individuals, the presence of gluten fragments in the lamina propria triggers an innate immune response (left), culminatingin tissue transglutaminase (tTG) release fromdamagedcells.Deamidated

gluten fragmentsare presented to CD4 + T cells (right),with subsequentactivation of both T H 2 response leading to B-cell proliferation and T H 1 response leading to the release of proinflammatory cytokines,migration of natural killer (NK) cells to the gut epithelium,andincreasedIELs,andultimately to theinsultofIECandCD71expression ontheapicalsideofIECwithsubsequentadditionalpassageofglutenfragmentsthrough the transcellular pathway. EGFR, epidermal growth factor receptor; IL, interleukin; INF, interferon; KGF, keratinocyte growth factor; TCR, T-cell receptor.

650 JAMA August 15, 2017 Volume 318, Number 7 (Reprinted)

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Celiac Disease and Nonceliac Gluten Sensitivity

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Table 3. Range of Sensitivity and Specificity and Use of Current Serologic Tests for Celiac Disease a







Application in Clinical Practice




First-line testing to screen for celiac disease b




First-line testing for celiac disease in patients with IgA deficiency




Second-line confirmatory test to screen for celiac disease




Not recommended for routine use because of poor sensitivity compared with IgG DGP




Not recommended for routine use because of poor sensitivity and specificity compared with IgA tTG and IgA EMA

Abbreviations: EMA, antiendomysial antibody; DGP, deamidated gliadin peptide; tTG, tissue transglutaminase.

a Adapted from Thawani et al. 41

b Should be sent with a baseline IgA level initially to ensure there is no IgA deficiency.

of patients with celiac disease have neurologic manifestations, psy- chiatric manifestations, or both. 39,40 Peripheral neuropathy is fre- quent, compared with healthy controls. The etiology may be attrib- utable to nutritional deficiencies suchas deficientvitaminB 12 , chronic inflammation, or an immune-basedmechanism. 40 In one study, neu- ropathy was diagnosed in 0.7% of patients with celiac disease, com- pared with 0.3% of controls. 41 Refractory celiac disease is defined as persistent or recurrent malabsorptive symptoms and villous atrophy despite strict adher- ence to a gluten-free diet for at least 6 to 12 months. Patients with refractory celiac disease may go on to develop uncommon but se- vere complications such as ulcerative jejunitis and enteropathy- associated T-cell lymphoma. 42

Nonceliac Gluten Sensitivity

The clinical symptoms of nonceliac gluten sensitivity begin after the ingestion of gluten-containing grains. Symptoms improve or disap- pear with withdrawal of these grains from the diet, and symptoms reappear after gluten challenge, usually within hours or days. The clinical gastrointestinal presentation of nonceliac gluten sensitivity is characterized by abdominal pain, bloating, bowel irregularity (di- arrhea, constipation, or both), while extraintestinal manifestations include patient report of a “foggy brain,”which is described as slowed thinking, memory disturbance, or reduced level of alertness, along with headache, joint andmuscle pain, fatigue, depression, leg or arm numbness, dermatitis (eczema or skin rash),andanemia (Table 2). 8,43

Assessment and Diagnosis

Celiac Disease

There has been an increase in the availability and use of accurate non- invasive tools for the diagnosis of celiac disease in the last 20 years. Their performance has been recently and comprehensively reviewed. 44,45 Recommendations for the use of each test and the sensitivityand specificityare summarized in Table 3.In practice,mea- surement of serum IgA antibodies to tissue transglutaminase (anti-tTG) (or IgG class in patients with IgA deficiency) is an excel- lent screening procedure with high sensitivity and specificity and is considered the first screening test that should be ordered in pa- tients in whom celiac disease is suspected. The IgA antiendomysial antibody determination is 98% specific for active celiac disease, but it should be used only as a confirmatory test because of cost and sub- jective interpretation, which may contribute to the more variable sensitivity. 44 Deamidated gliadin peptides—antibodies of the IgG class—have a sensitivity and specificity close to IgA anti-tTG anti- bodies and should be used as the initial screening test for patients withIgA deficiency.Given the highlyaccurate testsavailable, the first- generation antinative gliadin antibody test should no longer be used

to evaluate for celiac disease. 44 HLA-DQ2 and HLA-DQ8 determina- tionmay be usefulwhen there is discrepancy between serologic stud- ies and histologic findings to better assess whether celiac disease is possible, because the disease, except in rare cases, cannot develop in individualswhoare negative for HLA-DQ2 and HLA-DQ8. 44 Figure 2 provides a diagnostic approach to celiac disease. Villous blunting on the small-intestinal biopsy can definitively establish the diagnosis of celiac disease and is recommended by the North American Society for Pediatric Gastroenterology, Hepatol- ogy, and Nutrition (NASPGHAN) and the American College of Gastroenterology (ACG). 46,47 The characteristic histologic changes associated with celiac disease include an increased number of in- traepithelial lymphocytes (>25 per 100 enterocytes), elongation of the crypts,and partial to totalvillousatrophy. 48 The EuropeanSociety for Pediatric Gastroenterology andHepatology (ESPGHAN) has pro- posed an algorithm for children whomeet specific criteria, for whom biopsy is not recommended. 4 For the biopsy to be omitted, chil- drenmust have signsand symptoms suggesting celiac disease,a posi- tive anti-tTG antibodies finding with a level greater than 10 times the upper limit of normal, a positive antiendomysial antibody find- ing obtained at a different time than the anti-tTG antibodies find- ing, and a HLA genotype compatible with celiac disease. 4 Specific diagnostic procedures such as double-balloon enteroscopy, video- capsule endoscopy, or magnetic resonance imaging are rarely used and may be indicated in the workup of complicated celiac disease when there are discrepancies between serology and histology re- sults or when a patient with celiac disease has persistent or wors- ening symptoms despite following a gluten-free diet.

Nonceliac Gluten Sensitivity

No specific biomarkers have yet been identified and validated for nonceliac gluten sensitivity. Clinicians should suspect nonceliac glu- ten sensitivity in a patient who presents with gastrointestinal or ex- traintestinal symptoms (Table 2) that appear to improve with a glu- ten-free diet. Since these symptoms also can be seen with celiac disease and, to a lesser extent, with wheat allergy, these conditions need to be preliminarily excluded with serologic and histologic evi- dence to focus on the suspicion of nonceliac gluten sensitivity. Until biomarkers are identified and validated, the diagnosis of nonceliac gluten sensitivity is confirmed in a research setting with a double- blind crossover gluten challenge. 49 In a clinical setting, cliniciansmay suggest a blinded gluten challenge during which a patient is given approximately 8 g of gluten (corresponding to approximately 2 slices of bread) or placebo for 1 week each, separated by a 1-week gluten-free washout period. Symptoms are monitored throughout the challenge. 49 A blinded challenge is not generally feasible in a clini- cal setting; therefore, for patients with fluctuating symptoms,

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Celiac Disease and Nonceliac Gluten Sensitivity

Figure 2. Proposed Screening Algorithm for Celiac Disease


Positive result

(villous blunting)

biopsy Positive result (villous blunting) Celiac disease Treatment 652 Patient with symptoms or signs consistent

Celiac disease



Patient with symptoms or signs consistent with celiac disease or at high risk of celiac disease (eg, positive family history, type 1 diabetes, Hashimoto thyroiditis, Down syndrome)

Measure total IgA and IgA tissue transglutaminase (tTG)
Measure total IgA and IgA tissue transglutaminase (tTG)
Measure total IgA and IgA tissue transglutaminase (tTG)
Measure total IgA and IgA tissue transglutaminase (tTG)

Measure total IgA and IgA tissue transglutaminase (tTG)

Measure total IgA and IgA tissue transglutaminase (tTG)
Measure total IgA and IgA tissue transglutaminase (tTG)
Measure total IgA and IgA tissue transglutaminase (tTG)
Measure total IgA and IgA tissue transglutaminase (tTG)
Measure total IgA and IgA tissue transglutaminase (tTG)
Measure total IgA and IgA tissue transglutaminase (tTG)
Measure total IgA and IgA tissue transglutaminase (tTG)

Negative IgA tTG result a

IgA tissue transglutaminase (tTG) Negative IgA tTG result a Total IgA < 7 mg/dL Total IgA
IgA tissue transglutaminase (tTG) Negative IgA tTG result a Total IgA < 7 mg/dL Total IgA
Total IgA < 7 mg/dL
Total IgA < 7 mg/dL
Total IgA ≥ 7 mg/dL Celiac disease unlikely
Total IgA ≥ 7 mg/dL
Celiac disease unlikely
Positive (≥ 20 U/mL) Measure IgG Negative (< 20 U/mL)

Positive (≥ 20 U/mL)

Measure IgG

Negative (< 20 U/mL)


deamidated gliadin



U/mL) Measure IgG Negative (< 20 U/mL)   deamidated gliadin   peptide Yes Persistent symptoms?


Persistent symptoms?

Negative result (normal duodenal histology or increase in intraepithelial lymphocytes and/or crypt hyperplasia)

Measure IgA antiendomysial antibody (EMA) Repeat IgA tTG Consider HLA-DQ2 and - DQ8 genetic testing

Measure IgA antiendomysial antibody (EMA) Repeat IgA tTG Consider HLA-DQ2 and -DQ8 genetic testing for celiac disease

HLA-DQ2 and - DQ8 genetic testing for celiac disease Negative EMA b or repeat IgA tTG
Negative EMA b or repeat IgA tTG test results
Negative EMA b or repeat
IgA tTG test results

Repeat EMA and IgA tTG tests in 3-6 mo






Positive IgA tTG result a
Positive IgA tTG result a

Perform duodenal

Positive EMA, b IgA tTG, and genetic testing results
Positive EMA, b IgA tTG,
and genetic testing results

Potential celiac disease Begin gluten-free diet

symptomatic assessment of a patient adhering vs not adhering to a gluten-free diet for at least 1 week is suggested. 49

Currently, a strict gluten-free diet remains the only available treat- ment for gluten-related disorders, but the time frame is different ac- cording to the specific disorder. It has been suggested that nonce- liac gluten sensitivity may be a transient condition. 49 Therefore, expert recommendation is that the gluten-free diet should be fol- lowed for a given period, eg, 12 to 24 months, before testing gluten tolerance again. Based on severity of symptoms, some gluten- sensitive patients without celiac disease may choose to follow a gluten-free diet indefinitely. 49 For patients with celiac disease, life- long implementation of a strict gluten-free diet is the only option; however, adhering to such a diet can be difficult, owing to minute amounts of gluten that may be present on gluten-free foods. These trace amounts can be as harmful as lack of adherence to a gluten- free diet. According to expert opinion, patients diagnosed with a glu- ten-related disorder should be monitored by a gastroenterologist andanexperienced dietician to counsel the patientand family in navi- gating the gluten-free diet. 50,51

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Downloaded From: by a University Paris 5 Descartes User on 08/15/2017


by a University Paris 5 Descartes User on 08/15/2017 No Consider HLA-DQ2 and - DQ8 testing

Consider HLA-DQ2 and -DQ8 testing if high risk for celiac disease

a Reference values for IgA tTG vary depending on the source of the tTG used (recombinant tTG vs tTG purified from human red blood cells) and kit-specific range (cutoff ranging from <4 U/mL to <20 U/mL).

b Cutoff for EMA is 1:5 dilution (subjective immunofluorescence method).

Acute and Long-term Management: Follow-up and Outcomes in Patients With Celiac Disease

In patients with celiac disease, nutritional markers should be evalu- ated at diagnosis, and abnormal findings should be reassessed after 1 year of adherence to a gluten-free diet. Up to 28% of chil- dren presentingwith celiac disease havea nutritional deficiency, such as iron (28%), folate (14%), vitamin B 12 (1%), or vitamin D (27%) de-

ficiency at diagnosis. 35 Adults presentingwith celiac disease are likely to have a nutritional deficiency, such as folate (20%), B 12 (19%), or zinc (67%); 32% had iron-deficiency anemia in 1 study. 7 Children’s growth should be routinely monitored. Current guidelines recom- mend follow-up serologic testing to assess dietary adherence and for use as a surrogate marker of mucosal recovery in children and adults. 4,46,47 Recommendations also support a baseline dual- energy x-ray absorptiometry scan for women and men older than

years diagnosed with celiac disease. 52

Serologic Follow-up in Patients With Celiac Disease

Celiac-specific autoantibody levels should be measured every 6 to

months after initiation of the gluten-free diet until they

normalize. 4,46,47 Once levels have normalized, it is presumed that

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Celiac Disease and Nonceliac Gluten Sensitivity

mucosal recovery, secondary to dietary adherence, has occurred. Al- though current guidelines according to the ACG, NASPGHAN, and ESPGHAN endorse and recommend the use of serology as a marker of dietary adherence and mucosal recovery, these tests have not been validated for this purpose. 4,46,47 Furthermore, recent work has reported that the sensitivity of IgA tTG to identify persistent enter- opathy after a patient with celiac disease has started a gluten-free diet is 43% to 83%. 53,54

Intestinal Biopsy in Patients With Celiac Disease

Currently available serologic tests may be inadequate to predict mucosal recovery in patients with celiac disease who follow a gluten-free diet. 54,55 In the United States, the Food and Drug Administration has prioritized the need to develop accurate surro- gate end points to assess mucosal recovery in patients with celiac disease. Although data evaluating pediatric mucosal recovery are limited, previous data suggested a more complete and faster heal- ing time in children compared with adults. 56 More recent data sug- gested that 5% to 19% of children with celiac disease who follow a gluten-free diet may have persistent enteropathy despite treat- ment with a gluten free diet for at least 1 year. 53,54 Irrespective of IgA tTG levels, 25% to 40% of adults did not achieve mucosal recovery after 2 years of following a gluten-free diet. 57,58 Persistent villous blunting was more common in older and male patients and less common in patients with higher educational attainment. 59 Given these findings, a follow-up endoscopy to ensure mucosal recovery in adult patients is recommended in some celiac centers. More studies are needed to evaluate the long-term complications associated with persistent villous blunting in adults and children with celiac disease before universal follow-up and treatment regi- mens are described. At this time, available treatment options for patients diagnosed with celiac disease with persistent villous blunt- ing despite a gluten-free diet include implementation of the gluten contamination elimination diet, which offers only fresh fruits, veg- etables, meat, and limited condiments or medical therapy with immunosuppressants, such as budesonide. 60,61 These interven- tions should be offered and monitored by a gastroenterologist with expertise in celiac disease, because both symptom improvement and resolution of the enteropathy are considered in the response to treatment.

Prognosis of Celiac Disease

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agnosed celiac disease have an increased rate of osteoporosis and hypothyroidism and had a lower body mass index and lower levels of ferritin and cholesterol compared with women with undiag- nosed celiac disease. 65 Last, infertility and recurrent abortion are re- ported as possible adverse pregnancy outcomes. 66


A number of studies have examined mortality in undiagnosed ce-

liac disease. Some showed increased mortality, while others did not. 67-69 A recent meta-analysis suggested that the overall malig- nancy risk in patients with diagnosed celiac disease was not el- evated, compared with the risk in general population–based controls. 70 However, individual cancers, such as lymphoprolifera- tive cancer and gastrointestinal cancers, 71,72 may still be positively associated with celiac disease.

Practical Questions

Should Family Members of People With Celiac Disease Be Tested?

First-degree family members of patients with celiac disease have up toa 15- to 25-fold higher frequency of developing celiac disease based on their genetics, compared with individuals without a first-degree family member with celiac disease. 6,73 For that reason, the ACG, NASPGHAN, and ESPGHAN suggest screening first-degree family members with or without signs or symptoms concerning for celiac disease. 4,46,47 Recommendations include initiation of testing by age 3 years and, if serologic testing results are negative, repeating testing throughouta patient’s lifetime. TheUSPreventiveServices Task Force recently released recommendations that screening asymptomatic patients with or without a known increased risk of celiac disease, in- clusive of familymembers,is not recommended,based oninadequate evidence regarding benefits and risks of this screening. 74,75

When Should Clinicians Check for HLA-DQ2 and HLA-DQ8 ?

Clinically, genetic testing for HLA-DQ2 and HLA-DQ8 may be help- ful to determine whether patients in high-risk groups, such as fam- ily members or patients with comorbid conditions such as autoim- mune thyroid disease, need screening for celiac disease. It also may be used for patients already following a gluten-free diet who have

not been accurately assessed for celiac disease and are hesitant to reintroduce gluten into their diet for an accurate diagnostic reevalu- ation. In these cases, if patients do not carry the HLA-DQ2 or HLA-DQ8 genes, they would not require further diagnostic workup

Implementation of the gluten-free diet is the only treatment for ce-


evaluate for celiac disease. Celiac genetic testing may be useful

liac diseaseand thereforeacts to prevent possiblemorbidityand pos-


complicated cases such as in patients with signs and symptoms

sible mortality associated with untreated celiac disease.

suggestive of celiac disease and with compatible histology but se- ronegative serology to solidify a diagnosis. 2 If patients are found to


Research by Cosnes et al 62 suggested that the implementation of a gluten-free diet in patientswith celiac diseasemay beassociatedwith a protective effect against autoimmune disease such as thyroid dis- ease. Researchers reported a lower cumulative risk of developing subsequent autoimmune disease in patients following a gluten- free diet compared with patients diagnosed with celiac disease not following a gluten-free diet for at least 10 years (6% [±2%] vs 15.6% [ ± 5.9%], respectively). 62 Additionally, 2 Italian studies 63,64 sug- gest that a gluten-free diet may decrease the prevalence of thyroid autoantibodies; however, whether it protects against hypothyroid- ism or hyperthyroidism remains to be established. Men with undi-

have compatible celiac genetics but other test results are normal, this places them among the nearly 40% of the general population

that carries one of these genes. These patients should continue to follow a gluten-containing diet unless they are diagnosed with

a gluten-related disorder.

How Does One Make a Diagnosis of Celiac Disease? What Serologic Tests Should Be Used?

Clinicians should start with serologic testing in patients presenting with signs and symptoms compatible with celiac disease or those who belong to a high-risk group (Table 2). Signs, symptoms, family history, and serologic results should be considered according to the

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© 2017 American Medical Association. All rights reserved.

Clinical Review & Education Review

algorithm shown in Figure 2 to make a diagnosis. At the time that celiac disease serology is tested, patients should have been follow- ing a gluten-containing diet for at least some months.

What Are the Most Common Manifestations at Celiac Disease Presentation?

The clinical presentation of celiac disease is heterogeneous; thus, there is not a “typical” presentation. Testing for celiac disease should be considered in patients who have gastrointestinal manifestations such as abdominal pain, bloating, diarrhea, and constipation. Extrain- testinal manifestations such as anemia, joint pain, osteoporosis, pe- ripheral neuropathy, fatigue, and headache are frequent (Table 2). In pediatric patients, testing should be considered for thosewith slow or poor growth, delayed puberty, or tooth enamel defects.

How Common Is Iron-Deficiency Anemia or Osteoporosis the Presenting Sign or Symptom? Which Patients With Iron-Deficiency Anemia or Osteoporosis Should Be Screened for Celiac Disease?

At the time of diagnosis, approximately 28% and 9% of children may present with iron deficiency and iron-deficiency anemia, respectively. 35 Up to 32% of adults present with iron-deficiency ane- mia, making it the second most common clinical presentation after diarrhea. 7,76 Patients with otherwise unexplained iron-deficiency anemia, in those who do not respond to oral iron therapy, should be tested for celiac disease. In adults, osteoporosis may be present in 10% of patients at celiac disease diagnosis. 76 However, the fre- quencywithwhich patients presentwith osteoporosis is likely under- reported, since most cases of osteoporosis will not be apparent un- til a clinical complication such as a spontaneous fracture occurs. Therefore, physicians should have a low threshold for testing for

Celiac Disease and Nonceliac Gluten Sensitivity

celiac disease in children and adults with unexplained, spontane- ous, or repetitive fracture.

Can a Gluten-Free Diet Be a Treatment for Situations That Do Not Belong to Gluten-Related Disorders?

There is no scientific evidence to suggest that a gluten-free diet is part of a healthier lifestyle or can be helpful to treat overweight or obesity. The incomplete digestibility of gluten (see “Pathophysiol- ogy” section) may explain why some people report nonspecific im- provement in well-being after starting the gluten-free diet. Further- more, gluten-containingcereals, particularlywheat,arealsoa primary source of FODMAPs (fermentable oligosaccharides, disaccharides, and monosaccharides and polyols), a group of highly fermentable but poorly absorbed short-chain carbohydrates and polyols. The reduction of FODMAPs associated with the gluten-free dietmay explain, at least in part, why some patients affected with irritable bowel symptoms may report amelioration of their symptoms after starting a gluten-free diet. 77 Self-diagnosis of nonceliac gluten sen- sitivity should be discouraged to avoid misdiagnosis and inappro- priate treatment.

to avoid misdiagnosis and inappro- priate treatment. Conclusions Celiac disease and nonceliac gluten sensitivity
to avoid misdiagnosis and inappro- priate treatment. Conclusions Celiac disease and nonceliac gluten sensitivity


Celiac disease and nonceliac gluten sensitivity are common. Al- though both conditions are treated with a gluten-free diet, distin- guishing between celiac disease and nonceliac gluten sensitivity is important for long-term therapy. Patients with celiac disease should be followed up closely for dietary adherence, nutritional deficien- cies, and the development of possible comorbidities.


Accepted for Publication: July 3, 2017.

Author Contributions: Drs Leonard and Fasano had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: All authors. Acquisition, analysis, or interpretation of data:

Leonard. Drafting of the manuscript: All authors. Critical revision of the manuscript for important intellectual content: All authors. Administrative, technical, or material support:

Leonard. Supervision: Sapone, Catassi, Fasano.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Catassi reported receiving fees for scientific consultancy from Dr Schär Institute. Dr Fasano reported receiving a grant for sponsored research from INOVA Diagnostics; receiving speaking fees from Mead Johnson Nutrition; and that he is cofounder of, and a stockholder in, Alba Therapeutics, which makes products for the treatment of autoimmune and inflammatory diseases. No other authors reported disclosures.

Submissions: We encourage authors to submit papers for consideration as a Review. Please contact Edward Livingston, MD, at Edward or Mary McGrae McDermott, MD, at


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